Degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are devastating disorders that encompass both wide ranges of clinical severity and ages of onset. Recently, genes involved in some familial forms of ALS (SOD1) and responsible for greater than 9% of SMA cases (SMN) have been identified. To date, however, no common mechanisms or molecular pathways have been determined that can explain the progressive neurodegeneration. The vast genetic heterogeneity observed in familial cases of ALS and the high proportion of sporadic cases (approximately 90% of patients) suggest that several different genes are necessary for the normal function and survival of motor neurons. Although some of these genes may be identified in humans, the exploitation of several well-defined mouse mutants affecting motor neuron survival provides a powerful alternative means to understanding disease susceptibility and progression. Neuromuscular degeneration, nmd, is an autosomal recessive mouse mutant characterized by severe hindlimb muscle atrophy due to progressive degeneration of spinal motor neurons. Our recent identification of the nmd gene by a position cloning approach and out proposed of a major genetic modifier of its phenotypic expression (Mnm) will allow us to experimentally determine the mechanisms responsible for motor neuron disease. Toward this goal, we are employing sophisticated genetic approaches to identify the critical cell-neuron disease. Toward this goal, we are employing a sophisticated genetic approaches to identify the critical cell-neuron disease. Toward this goal, we are employing a sophisticated genetic approaches to identify the critical cell-cell types that require nmd gene activity in chimeric mice and to isolate the Mnm modifier gene by a positional and functional cloning strategy. Our ability to manipulate the severity of the phenotype genetically with at least one modifier gene suggests that a molecular pathways exists with the potential for genetic or clinical intervention. The steps we will take to analyze the nmd and Mnm modifier genes will be 1) to determine the cellular basis of motor neuron degeneration in nmd mice by using chimeras t examine the cell autonomy of neuronal death, 2) to determine the allelic status of Mnm gene in several strains of inbred mice and to test whether Mnm/C modifies other mouse models of neurodegeneration, and 3) to identify the Mnm gene by a positional cloning approach employing high resolution genetic and physical mapping and transgenic rescue in nmd ES cell derived mice. Thus, the nmd mouse and Mnm modifier gene provide a unique opportunity to identify the underlying processes of neurodegeneration and provide possible entry points in which to intervene in the disease pathway.